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Review Article

A Qualitative and Quantitative Systematic Review of Preemptive Analgesia for Postoperative Pain Relief: The Role of Timing of Analgesia

Møiniche, Steen M.D.*; Kehlet, Henrik M.D., D.M.Sc.†; Dahl, Jørgen Berg M.D., D.M.Sc.‡

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THE concept of preemptive analgesia to reduce the magnitude and duration of postoperative pain was paved in 1983 by Woolf, 1 who showed evidence for a central component of postinjury pain hypersensitivity in experimental studies. Subsequently, an overwhelming amount of experimental data demonstrated that various antinociceptive techniques applied before injury were more effective in reducing the postinjury central sensitization phenomena as compared with administration after injury. 2 Finally, these promising experimental findings were taken into clinical testing of the hypothesis. Although early reviews of clinical findings were mostly negative, 3–5 there is still a widespread belief of the efficacy of preemptive analgesia among clinicians.
The definition of preemptive analgesia has varied, thereby causing confusion and misunderstanding of the concept. 6 Because the original observations in experimental studies suggested that timing of analgesic treatment was important to obtain efficient reduction of postinjury pain hypersensitivity phenomena, we performed an updated review of studies to compare the role of timing of analgesia i.e., preoperative versus intraoperative or postoperative initiation of analgesia. In this review we are not considering studies designed to compare preemptive analgesia versus no treatment. We have only included double-blind, randomized, controlled trials of identical or very similar analgesic regimens, where the only difference between study groups was timing of analgesia.
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Literature Search
Reports of randomized controlled trials of preemptive analgesia for acute or chronic postoperative pain relief were systematically sought using the Cochrane Library 2000 § ( and the MEDLINE (; 1966–2000) databases without language restriction. We used different search strategies with free text combinations, including the following search terms: preemptive analgesia, preemptive analgesia, prophylactic pain treatment, preoperative treatment, postoperative pain, postoperative analgesia, chronic pain, and long-term pain. The last search was performed on December 30, 2000. Reference lists of retrieved reports and review articles were hand-searched for additional papers. No abstracts, correspondences, or unpublished observations were included. Authors were not contacted for original data.
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Inclusion and Exclusion Criteria and Data Extraction
Reports that were included consisted of double-blind randomized comparisons of identical or nearly identical analgesic regimens initiated before versus after surgical incision for postoperative pain relief with or without the use of a double dummy.
Reports that were excluded included trials of comparisons of preoperative treatment with placebo or no treatment, and trials of comparisons of preoperative with preoperative plus postoperative treatment. Such studies provide no evidence for a preemptive effect, i.e., if timing of the initiation of the pain treatment is of importance. 5
We developed standard data collection sheets to record details of trial design, interventions, and outcome measures for every trial. Each report meeting the inclusion criteria was read independently by two of the authors and scored using a three-item, 1–5 quality scale. 7 Consensus was subsequently achieved. If the reports were described as randomized, one point was given, and an additional point was given if the method of randomization was described and adequate (computer-generated, table of random numbers, etc.), but one point was deducted if randomization was inappropriate (alternate randomization, randomization according to weekday, etc.). If studies were described as double-blind, one point was given, and an additional point was given if blinding was described and appropriate (use of double-dummy, blinded pharmacy manufactured ampoules, etc.), but one point was deducted if blinding was inappropriate. Finally, reports that described the numbers and reasons for withdrawals were given one point. By definition, studies without randomization and blinding were excluded. Thus, the minimum score of an included clinical trial was 2, and the maximum score was 5.
Each trial was assessed for different measures of internal sensitivity. First, trials were checked for magnitude of pain intensity. Because it is difficult to detect an improvement with low or no pain, it was noted if pain scores were less than 30 mm on a visual analog scale (VAS) or less than moderate pain on a verbal rating scale or similar score. 8 Second, it was noted if a power calculation of the statistical tests was performed. Trials with sample sizes less than 10 patients per treatment group were not considered. 9
Use of other intraoperative analgesic treatment (which in theory may preempt pain in the postsurgery treatment group) was noted but not regarded to invalidate the clinical relevance of trials, since common anesthetic practice often includes analgesic use (e.g., intraoperative fentanyl).
Data on postoperative pain and analgesic consumption were extracted for each report. Finally, information about type of anesthesia (general, regional) and number of patients enrolled was taken from each report.
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Data Handling
Qualitative analysis of postoperative effectiveness was evaluated by significant difference (P < 0.05 as reported in the original investigation) in pain relief using pain scores, time to first analgesic request, and consumption of supplementary analgesics between the presurgical and postsurgical treatment groups, and by assessment of the clinical importance of observed differences. The plot of L'Abbéet al.9 of VAS pain scores with preemptive versus postsurgical regimens was used as a graphic means of exploring the consistency of efficacy and the homogeneity of the data whenever possible.
Quantitative analysis of combined data were intended by calculation of the weighted mean difference (WMD) of VAS pain scores between treatment groups (using the Review Manager software, version 4.0, the Cochrane Collaboration; The Nordic Cochrane Center, Copenhagen, Denmark). The weight given to each study in this analysis (i.e., how much influence each study had on the overall results) was determined by the precision of its estimate by taking into account study size and SDs of the VAS scores in the individual trials. For the current use, a mean VAS for each treatment group was calculated in every trial from all available recordings performed within 24 h after surgery. Verbal rating pain scores and similar scores were converted to VAS pain scores (e.g., a four-point verbal rating score including no, light, moderate, and severe pain was converted to 0, 25, 50, and 75 mm VAS, respectively). The possibility was recognized that data only would allow a qualitative analysis. Finally, the trials were stratified according to the type of drug (opioid, local anesthetic, N-methyl-d-aspartate [NMDA] receptor antagonist, nonsteroidal antiinflammatory drug [NSAID]), mode of administration (systemic, neuraxial, peripheral nerve block, or wound infiltration), and, if possible, to surgical procedure.
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Ninety-three randomized clinical trials of preincisional versus postincisional analgesic regimens for postoperative pain control were identified. Of these, 11 studies were excluded because of lack of appropriate blinding or randomization 10–18 or use of different analgesic doses preoperatively and postoperatively. 19,20 Two articles were not available through the Danish University Library (Copenhagen, Denmark) or the British Library 21,22 (London, United Kingdom), leaving 80 reports for analysis. Studies excluded are summarized in the Appendix.
The remaining studies could be divided into 20 trials of systemic NSAIDs, 8 trials of systemic opioids, 8 trials of systemic NMDA receptor antagonists, 24 trials of epidural, caudal, or intrathecal analgesia, and 20 trials of peripheral local anesthetic use (wound infiltration or nerve block) or combinations of treatment.
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A total of 3,761 patients, of which 1,964received preincisional treatment, were studied. The range ofthe number of patients included in the studies was 10(in a crossover trial) to 128. The median quality scorewas 4 (range, 2–5) in trials with significantdifferences in pain relief between the treatment groups and 4(range, 2–5) in trials with no significant differences.The percentage of trials with a significant finding in favor of preemptive analgesia did not differ between trials of high quality (score, 4–5) and trials of lower quality (score, 2–3) (P = 0.67, Fisher test). Details of included studies are shown in tables 1–7 and figures 1–4.
Quantitative analysis was performed on the mean of VAS pain scores recorded within 24 h after surgery for each treatment modality. In five trials, verbal rating scores were converted to VAS scores (two trials of NSAID and three trials of local infiltration). Data on analgesic consumption and time to first analgesic request only allowed a qualitative analysis because of the variety of analgesics, doses, and outcome reporting used. Instead, any statistical difference between treatments regarding these measures was extracted from the original reports and documented in table format as performed previously for other qualitative systematic reviews. 23–25
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Acute Postoperative Pain
Nonsteroidal Antiinflammatory Drugs.
Twenty trials comparing preincisional with postincisional NSAID or paracetamol 26 using a parallel or crossover design 26–29 were identified. Various odontologic, abdominal, and orthopedic procedures were studied. The NSAIDs were diclofenac, 27,30–33 naproxen, 28,34 flurbiprofen, 35 ketorolac, 36–42 ketoprofen, 43,44 diflunisal, 29 and ibuprofen 45 used in clinically relevant doses (table 1). Fentanyl, 30,31,33,36,38,39,42–44 alfentanil, 34,37 local anesthetics, 26–29,33,35,45 or nitrous oxide 30,31,36–44 were, as a part of the anesthesia, coadministered intraoperatively in all trials.
In two trials, pain scores were significantly improved immediately after surgery by preemptive compared with postoperative treatment. 36,41 In none of the other trials were improvements observed (fig. 1A). Quantitative analysis with the calculation of the WMD of VAS scores between treatment groups using a fixed-effect model (as test for heterogeneity was nonsignificant, P = 0.78) was not significant (WMD, 0 mm; 95% confidence interval [CI], −2 to 2 mm;fig. 2A) with 14 trials. In the remaining six trials, one of which showed reduced pain scores, 41 there was a lack of dispersion measures for the calculation. 27,31,35,37,41–42
In one trial, 31 the number of patients needing rescue analgesics and time to first request was improved by 28% and 1.5 h, respectively. In two other studies, patient-controlled analgesia–morphine and time to first analgesic request were statistically improved by 6 mg over 6 h 36 and 49 min, 44 respectively. In none of the other trials was demand for supplementary analgesic different between treatment groups.
Power analysis of the statistical tests was only available in five trials, 30,34,36,40,44 with a power of 75–95% of detecting a difference of 15–25 mm VAS at the 5% significance level. Furthermore, intensity of pain scores was low in eight trials (< 30 mm VAS), 27–29,33,35–36,40,45 which might have impaired internal sensitivity.
In conclusion, some aspects of postoperative pain control were improved by preemptive treatment in 4 of the 20 trials. Overall, the data demonstrated preemptive NSAIDs to be of no analgesic benefit when compared with postincisional administration of these drugs.
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Intravenous Opioids.
Eight trials with nine treatment arms were identified comparing preincisional with postincisional administration of morphine (10 mg or 0.15–0.3 mg/kg), 46–48 fentanyl (10 μg/kg), 49 alfentanil (40–70 μg/kg), 50,51 sufentanil (1 μg/kg), 49,52 or pentazocine (30–60 mg) 53 (table 2). In all trials, the surgical procedure was abdominal hysterectomy. In none of the trials was other intraoperative analgesics (beside the test drugs) administered except for nitrous oxide in all studies.
In no study were pain scores significantly reduced in the preemptive group (fig. 1B). In contrast, quantitative analysis of pain scores using a fixed-effect model (P = 0.75 in test for heterogeneity) revealed that the WMD in VAS scores between study groups was statistically significant in favor of the postoperative groups (5 mm; 95% CI, 1–9 mm;fig. 2B).
Supplementary analgesic consumption was significantly reduced in two studies in the preemptive group, averaging 10 mg morphine over 24 h 46 and 12 mg morphine 50 from 48 to 72 h, but not from 0 to 6, 6 to 12, 12 to 24, or 24 to 48 h postoperatively, rendering interpretation difficult. Time to first analgesic request was evaluated in only one trial 50 and was not different between study groups.
Intensity of pain scores was considered adequate (> 30 mm VAS) in all trials. However, in only three trials was power analysis of the statistical tests performed, 48–50 revealing an at least 80% power to detect a reduction in VAS scores of 20 mm 49,50 or decrease in opioid consumption of 30%48 at the 5% significance level.
In conclusion, no improvement in postoperative pain control was observed after preemptive administration of systemic opioids.
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Intravenous or Intramuscular N-methyl-d-aspartate Receptor Antagonists.
Eight trials were identified comparing preincisional with postincisional ketamine 54–59 or dextromethorphan 60,61 in a variety of surgical procedures (table 3). Ketamine was administered in doses of 0.15–1 mg/kg and in two trials continued with intraoperative infusion of 10 μg · kg−1 · min−1 in the preemptive group, of which one was negative and one positive. 54,56 Dextromethorphan was given in doses of 40 mg to 5 mg/kg (mean, 275 mg). Coadministered analgesic drugs included intraoperative fentanyl, alfentanil, or sufentanil in seven trials 55–61 and nitrous oxide in five trials. 54–58
The worst pain score was significantly reduced by 20 mm VAS in one trial of dextromethorphan. 61 In the seven other trials, no effect on pain scores was observed (fig. 1C). The WMD calculated by use of a random-effect model (P < 0.05 in test for heterogeneity) was not significant (WMD, −2 mm; 95% CI, −8 to 4 mm;fig. 2C).
Supplementary analgesic consumption was significantly reduced by preemptive analgesia in three trials (one ketamine study 54 and the two dextromethorphan trials 60,61) by 40–70%, corresponding to 15–25 mg morphine 54,60 and 57 mg pethidine 61 over a 24–48-h observation period. In the five other trials (of ketamine), no effect 56–59 or increased analgesic consumption 55 was observed compared with the postincisional groups. Time to first analgesic request was evaluated in only one trial and was prolonged by 11 h by preemptive treatment. 61
Power analysis was performed in three trials 55,57,60 and showed an 80% power to detect a difference of 30% or 5 mg/24 h of morphine at the 5% significance level. Intensity of pain scores were greater than 30 mm VAS in all except for one trial. 59
In conclusion, no improvement in postoperative pain control was observed from preemptive systemic ketamine. Both studies on dextromethorphan were positive, but the data are too sparse to reach a definitive conclusion.
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Epidural, Caudal or Spinal Regimens.
Eighteen trials of presurgically versus postsurgically initiated epidural analgesic regimens were identified. These could be divided into trials of single-dose analgesic regimens 62–71 and trials of continuous analgesic regimens extending 24–72 h into the postoperative period. 72–79 Furthermore, five trials of caudal analgesia in children 80–84 and one trial of intrathecal anesthesia–analgesia 85 were found eligible for analysis.
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Single-dose Epidural Analgesia.
Ten trials with 11 treatment arms were identified comparing different preemptive versus postincisional single-dose epidural analgesic regimens. In four trials, epidural fentanyl (4 μg/kg) 63 and morphine (2–4 mg or 0.05 mg/kg) 65,68,71 were evaluated. In three trials, 64,66–67 epidural bupivacaine (0.5%, 15–20 ml) was studied, in three trials, combined epidural opioid (fentanyl or morphine) and local anesthetic (bupivacaine or mepivacaine), 62,69,71 and in one trial, epidural morphine (2 mg) plus ketamine (60 mg). 70 As a part of a balanced analgesic regimen, systemic NSAID was administered in two studies. 62,67 Coadministered analgesics included intraoperative alfentanil, fentanyl, or morphine in four trials 62,65,58,71 and nitrous oxide in eight trials. 62–66,69–71 Surgical procedures were major thoracic and abdominal (table 4).
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Epidural Opioid Regimens.
Pain scores were significantly reduced over 24 h by preemptive analgesia in one trial, 65 but only at six 63 and 18 h, 68 respectively, and not at 2, 4, 8, 10, 24, or 48 h postoperatively in two 63,68 of a total of four trials–treatment arms. 63,65,68,71 Analgesic demand was significantly reduced between 12 and 50%65,68 and by 14 mg of patient-controlled analgesia–morphine from 12–24 h 63 in the preemptive groups in three trials.
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Epidural Local Anesthetic Regimens.
Visual analog scale pain scores were not different between study groups in any of three trials. 64,66–67 Patient-controlled analgesia–morphine consumption in the preemptive group was significantly reduced by 16 mg over 24 h in one trial 64 but significantly higher in another trial. 67
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Combined Epidural Regimens.
Pain scores were not different between study groups in any of four trials–treatment arms. 62,69–71 Analgesic demand or number of patients requesting analgesics was significantly reduced between 33 and 48% in the preemptive groups in two trials 70,71 but only by 16 mg over 96 h in another trial. 62
Quantitative analysis, which was only possible with seven trials (eight treatment arms) because of lack of dispersion measures, revealed a nonsignificant WMD of mean VAS pain scores recorded over 24 h of −4 mm (95% CI, −9 to 2 mm; random effect mode;P = 0.04 in test for heterogeneity;figs. 3A and 4A). In two of the three trials not included in the WMD calculation, 67–68,70 no significant difference in VAS was observed at any time during the postoperative course supporting the quantitative estimate.
Power analysis of the statistical tests revealing a 90% power was available in two trials, 63,67 although without information of the minimal relevant difference (e.g., number of millimeters VAS), not to be overlooked. Furthermore, in one negative 62 and one positive 68 trial, low pain scores may have impaired internal sensitivity.
In conclusion, the quantitative analysis of mean VAS pain scores showed no significant reduction by preemptive single-dose epidural analgesia with opioid, local anesthetic, or a mixture. However, significant reductions in analgesic demand were demonstrated in 7 of 11 treatment arms.
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Continuous Epidural Analgesia.
Eight trials were identified 72–79 comparing different preemptive versus postincisional initiated continuous epidural regimens that extended 24–72 h into the postoperative period.
The regimens investigated included bolus epidural bupivacaine (0.5–0.75%, 8–18 ml) 73–75 plus morphine (2 mg), 74,75 epidural mepivacaine (1.5–2%, 4–15 ml) 76–79 plus morphine (4 mg) 78 or buprenorphine (0.1 mg), 76 and bolus epidural morphine (1.5 mg) plus ketamine (20 mg). 72 These were in the postoperative course followed by continuous epidural bupivacaine (5–10 mg/h) plus morphine (0.2–0.5 mg/h) or fentanyl (10–12 μg/h), 73–75,78,79 epidural mepivacaine (17–60 mg/h) 76,77 plus buprenorphine, and by combined epidural morphine (1 mg), ketamine (10 mg), and lidocaine (32 mg) every 12 h. 72 Coadministered analgesics consisted of fentanyl or alfentanil 73–75,78 and nitrous oxide 72,74–79 in four and seven trials, respectively. The surgical procedures were thoracotomy, major abdominal, and total knee replacement. For details, see table 5.
Visual analog scale pain scores were significantly reduced at certain time points in three trials within the first 72 h, 72,77,79 ranging between 8 and 17 mm on a VAS scale. No differences between groups were observed in the other trials (fig. 3B). Quantitative analysis of WMD of mean VAS scores recorded within 24 h was not significant (WMD, −3 mm; 95% CI, −10 to 5 mm; calculated using a random-effect model as P = 0.0002;fig. 4B). Supplemental patient-controlled analgesia–morphine consumption was significantly reduced by 3 mg over 24 h in only one trial. 72
Intensity of pain scores was considered adequate (> 30 mm VAS) in negative trials 73–76,78 and not a cause of possible insensitivity (although low [< 30 mm VAS] in two of the positive trials). 72,79 Power analysis was performed in only four trials, 73,75,77–78 revealing an 80% power to detect a 12–23-mm difference in VAS at the 5% significance level.
In conclusion, the results showed no overall improvement in postoperative pain relief with preemptive versus postincisional continuous epidural analgesia.
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Caudal and Intratheal Analgesia.
Five trials comparing preemptive with postincisional caudal block were identified. 80–84 The analgesics–anesthetics investigated were bupivacaine (0.25%, 0.5–0.8 ml/kg) 80,82–84 plus morphine (0.02 mg/kg), 83 and lidocaine (1%, 0.5 ml/kg). 81 In none of the trials was other intraoperative analgesics administered except for nitrous oxide in all studies. The surgical procedures consisted of hernia repair, orhidopexy, circumcision, and operation for club foot deformities (table 6).
Only in the trial of combined caudal bupivacaine and morphine 83 pain scores and analgesic demand were significantly reduced by the preemptive treatment, ranging 50% and 1 mg of morphine over a 24-h observation period. In no other trials were differences between treatment groups observed. 80–82,84
In one trial, preoperative spinal bupivacaine (15 mg) was compared with an identical postsurgical treatment in patients undergoing abdominal hysterectomy with general anesthesia. 85 No difference in pain scores were observed between treatment groups, but morphine consumption was significantly greater from 0 to 12 h after surgery in the preemptive compared with the postincisional group.
In conclusion, preemptive treatment was ineffective in four of five studies of caudal block and in the one study of intrathecal block.
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Peripheral Local Anesthetics.
Twenty trials comparing preemptive with postincisional application of peripheral local anesthetics were found eligible for analysis. These could be divided into trials of wound infiltration, peripheral nerve block, and intraperitoneal infiltration.
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Wound Infiltration.
Sixteen trials compared preoperative incisional local anesthetics with similar postincisional administration. 86–101 Bupivacaine (0.25–0.5%), ropivacaine (0.75%), and lidocaine (1–1.5%) were administered in volumes between 4 and 45 ml depending on the extent of the surgical incision and type of procedure. Intraoperative fentanyl or alfentanil and nitrous oxide were coadministered in 10 87–90,92,93,96–98,101 and 13 studies, 86–91,94,95,97–101 respectively. Evaluated surgical procedures were hernia repair, appendectomy, hysterectomy, tonsillectomy, total knee replacement, laparoscopy, breast biopsy, and odontologic surgery (table 7).
Pain scores were significantly reduced 24 h after surgery in the preemptive group in one trial 101 and at certain time points in the postincisional group in two other trials. 93,98 In the other trials, no differences in pain scores between groups were observed (fig. 3C).
Quantitative analysis was only performed with 14 trials because of lack of dispersion measures in the last two trials. 86,92 Using a fixed-effect model (P = 0.29), the WMD of VAS pain scores between treatment groups was nonsignificant (WMD, 0 mm; 95% CI, −3 to 4;fig. 4C).
Analgesic demand was significantly reduced by 50% over a 6-h observation period in one trial, 86 and time to first analgesic request was prolonged by 4 h in another trial 101 in the preemptive compared with the postsurgical treatment groups. In none of the other trials were significant differences observed between study groups.
A number of studies suffered from low internal sensitivity because of low pain scores in either group. 94,95,99 Furthermore, statistical power analysis was only performed in seven of the trials, 86,90,93–97 revealing an 80–90% power of detecting a difference of 10–15 mm VAS. In summary, there is no evidence for improved pain relief with preemptive local anesthetic wound infiltration compared with a similar postincisional administration.
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Peripheral Nerve Blocks and Intraperitoneal Local Anesthetic.
Three trials investigated an ilioinguinal iliohypogastric nerve block in patients undergoing cesarean delivery, 102 axillary block in hand or forearm surgery, 103 and intercostal nerve block in patients undergoing thoracotomy. 104 In the latter study, preincisional versus postincisional intravenous morphine and intramuscular diclofenac was coadministered using a multimodal approach 104 (table 7).
No significant difference in pain relief was observed after cesarean section, but results were difficult to interpret because of technical difficulties in obtaining a sufficient block in the preemptive group and because of low pain scores in either group. 102 In the trial of axillary block, postoperative pain and analgesic demand were improved in the postincisional compared with the preemptive group. 103 In contrast, pain scores were reduced during a vital capacity breath test but not at rest, and analgesic demands were not improved by preemptive versus postincisional treatment in the trial of thoracotomy. 104
Finally, pain scores and demand for supplementary ketorolac were reduced by 10 mm VAS and 13 mg, respectively, in the preemptive treatment group from 8 to 24 h after surgery in one trial of topical intraperitoneal 0.5% bupivacaine. 105 In conclusion, the limited data available do not allow conclusions as to a positive effect of preemptive analgesia with peripheral nerve blocks or intraperitoneal local anesthetic.
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Chronic Postoperative Pain
Only one study was available comparing preemptive versus postincisional continuous epidural mepivacaine in patients undergoing thoracotomy. 77 Pain scores and the percentages of pain-free patients were improved in the preemptive group at 3 and 6 months after surgery in a fashion parallel to findings on acute pain scores.
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Overall Conclusion
Statistical improvements in postoperative pain relief by the preemptive compared with the postincisional treatment were observed in some parameters or time points in 24 of 80 (82 treatment arms) trials. Quantitative analyses of WMD of average VAS pain scores recorded within 24 h after surgery were in no case significant in favor of the preemptive treatment.
The review revealed a lack of evidence for preemptive treatment with NSAIDs, intravenous opioids, intravenous ketamine, peripheral local anesthetics, and caudal analgesia to be of any benefit with respect to postoperative pain relief compared with a similar postincisional treatment. Results from trials of single-dose epidural treatment were inhomogeneous, with more than half of the trials showing statistically significant, but in most cases small, improvements with preemptive analgesia. Results from a third of the trials of continuous epidural analgesia demonstrated, at certain time points, statistically improved pain relief or analgesic demand by preemptive treatment, but overall interpretation of all continuous epidural regimens did not support the hypothesis that preemptive analgesia is of greater benefit than analgesia administered after the onset of the surgical procedure.
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We tested the clinical evidence for timing of analgesia to improve postoperative pain control in the early and long-term postoperative period in this systematic review. Only trials designed to compare similar preincisional and postincisional treatment were included, excluding a number of studies from the analysis. 19,20 We chose to include a statistical combination of data from the independent trials in a quantitative analysis in addition to the qualitative systematic review. This was done to produce a single estimate of the effect of the intervention and to help resolve disparities between conflicting studies. 106 However, only data on pain scores could be quantitatively analyzed. For the quantitative analysis, we chose to use recordings of average pain scores within the first 24 h postoperatively as we considered this to be a clinically relevant measure and a way to overcome difficulties if only one of several recordings were found significant in an individual study. This analysis may therefore have overlooked potential positive findings within the immediate postoperative period or during the next few postoperative days. With these assumptions, our qualitative and quantitative analysis should be viewed together to achieve an overall synthesis of the results.
A concern was the lack of internal sensitivity and power in some of the negative studies. Validity criteria for the included studies was a number of 10 or more patients per treatment group. 9 Internal sensitivity was evaluated with respect to pain intensity, since it has been recognized that it is difficult to detect an improvement with low or no pain. 8 Furthermore, similar pain scores in study groups receiving active treatment may reflect similar analgesic effects or no effects at all. Inclusion of a placebo group in the comparison would solve the problem with similar or low pain scores. 107 Although pain intensity was low in some trials, and because only rather few trials on preemptive analgesia did include a placebo group, we did not exclude such trials from the analysis, but instead documented studies with low pain scores in the Results and in the tables.
Criticism has previously been raised against a number of negative studies in which both study groups received intraoperative opioid. 108 Such treatment may have caused a similar preemptive effect in both the preoperative and postoperative treatment groups and thereby contributed to the lack of difference in postoperative pain control between groups. Furthermore, various anesthetics have been demonstrated to suppress spinal sensitization in experimental studies. 109 However, such studies have not been excluded from our analysis, since the objective was to investigate if preemptive techniques combined with conventional intraoperative management, which often includes intraoperative opioids or nitrous oxide, can improve postoperative pain control. Although trials were quality assessed, potential pitfalls in individual trials, such as inadequacy of used statistics, may have remained unidentified. Finally, pooling of data from a class of analgesics (e.g., NSAIDs) may blur a possible effect of one specific agent (e.g., ketorolac). However, no such pattern was observed.
A total of 80 trials meeting the strict inclusion and exclusion criteria were identified. The trials were divided into those of NSAIDs, intravenous opioids, parenteral NMDA receptor antagonists, epidural analgesia (single dose or continuous), caudal analgesia, and peripheral local anesthetics. A common feature of the analysis was that timing of analgesia did not influence the quality of postoperative pain control, whatever the type of preemptive analgesia. This conclusion may have clinical relevance. It implies that NSAIDs should not routinely be given preemptively because of the lack of enhanced analgesic effects and because of potential adverse effects such as increased intraoperative bleeding with the preoperative treatment compared with postoperative treatment.
With regard to NMDA receptor antagonists, trials of ketamine were uniformly negative, while the only two existing studies of dextromethorphan were positive of a preemptive effect. Further data are obviously needed to allow a final conclusion as to the clinical recommendation of preemptive treatment with dextromethorphan.
Pain control was, at certain time points, improved by preemptive analgesia in 7 of 11 treatment arms of trials of single-dose epidural analgesia. However, validity and clinical relevance was questionable in several cases and difficult to interpret. Results were therefore considered to reveal a lack of evidence for any important effect (rather than evidence for lack of effect) with preemptive analgesia. Preemptive continuous epidural treatment extending into the postoperative period might theoretically have an improved capacity to reduce nociceptive input and thereby central neuroplasticity caused not only by incision and on-going surgery but also by postsurgical inflammation. However, the results were uniformly negative. In the few studies with improved analgesia, this was only observed at certain time points and not in the overall quantitative analysis. An explanation for the negative findings of continuous epidural regimens may be that, despite continuous treatment, it was insufficient to prevent the development and maintenance of injury-induced central sensitization.
It is widely assumed that preemptive analgesia may reduce the risk of developing chronic postoperative pain. This assumption may be supported by data suggesting that patients with high intensity of acute postoperative pain scores also have a higher risk of developing a chronic pain state. 110 In the only trial to compare the effect of identical preincisional versus postincisional treatment 77 on long-term pain, the percentage of patients with pain at 6 months postoperatively was significantly reduced. Obviously, more data are needed, and in other trials of preemptive treatment versus no treatment in prostatectomy, 20 thoracotomy, 111 or amputation, 112 only one demonstrated an effect on chronic postoperative pain. 20 However, in this study, 20 the follow-up rate was low (65%) and with a diversity between pain and activity scores at the different follow up intervals, making interpretation difficult.
It may be considered surprising and disappointing that the overall conclusion of this systematic review has been negative as to a potential beneficial effect of preemptive analgesia on postoperative pain. The issue of preemptive analgesia for postoperative pain relief has been a topic of several articles and editorials, in which terminology and definition has varied, thereby creating much of the controversy about this concept. 6,108,113 The concept has been further complicated by mixing results from trials of preincisional versus postincisional treatment and trials of pretreatment versus no treatment. 6 A number of suggestions have been offered to explain negative results: outcome measurement problems, too low or too high noxious stimulation induced by the surgical procedure, insufficient afferent blockade–analgesia, insufficient central inhibition, and insufficient duration of the treatment. 6,108,113,114 The current analysis of clinical trials has only focused on one aspect of this discussion, namely, whether timing of conventional analgesic therapy, i.e., preinjury versus postinjury initiation of analgesia, has a clinically significant impact on postoperative pain relief. One conservative conclusion that may be drawn from this review is that there is no need for further trials to investigate the role of timing of preemptive single-dose (short-lasting) analgesic treatment on the postoperative pain pattern. Furthermore, only three of eight trials investigating preemptive continuous epidural treatment extending into the postoperative period demonstrated improved pain relief at certain time points. Thus, overall results are also negative when timing is considered as the variable in prolonged analgesic treatment. It is important to realize, however, that these conclusions do not preclude a possible beneficial effect of an aggressive, perioperative, analgesic intervention on short- and long-term pain after surgery. We suggest that future studies redirect their focus from timing of perioperative analgesia (preemptive analgesia) to protective analgesia, aimed at the prevention of pain hypersensitivity (pathologic pain). These studies should investigate the effects of intensive and prolonged, multimodal analgesic (“protective”) interventions versus less aggressive, conventional perioperative analgesia on immediate and late postoperative pain.
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Xie, WR; Strong, JA; Meij, JTA; Zhang, JM; Yu, L
Pain, 116(3): 243-256.
American Journal of Health-System Pharmacy
Postoperative pain management: A practical review, part 1
Strassels, SA; McNicol, E; Suleman, R
American Journal of Health-System Pharmacy, 62(): 1904-1916.
Surgical Endoscopy and Other Interventional Techniques
A procedure-specific systematic review and consensus recommendations for postoperative analgesia following laparoscopic cholecystectomy
Kehlet, H; Gray, AW; Bonnet, F; Camu, F; Fischer, HBJ; McCloy, RF; Neugebauer, EAM; Puig, MM; Rawal, N; Simanski, CJP
Surgical Endoscopy and Other Interventional Techniques, 19(): 1396-1415.
Anasthesiologie & Intensivmedizin
The role of peripheral and central sensitisation in the maintenance and development of postoperative pain
Pogatzki-Zahn, EM
Anasthesiologie & Intensivmedizin, 47(): 638-+.

Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Effect of short-term postoperative celecoxib administration on patient outcome after outpatient laparoscopic surgery
White, PF; Sacan, O; Tufanogullari, B; Eng, M; Nuangchamnong, N; Ogunnaike, B
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 54(5): 342-348.

British Journal of Anaesthesia
Pre-incisional epidural ropivacaine, sufentanil, clonidine, and (S)+-ketamine does not provide pre-emptive analgesia in patients undergoing major pancreatic surgery
Gottschalk, A; Freitag, M; Steinacker, E; Kreissl, S; Rempf, C; Staude, HJ; Strate, T; Standl, T
British Journal of Anaesthesia, 100(1): 36-41.
Acta Anaesthesiologica Scandinavica
The ketamine enigma
Persson, J
Acta Anaesthesiologica Scandinavica, 52(4): 453-455.
Anesthesia and Analgesia
Low-Dose Systemic Bupivacaine Prevents the Development of Allodynia After Thoracotomy in Rats
Shin, JW; Pancaro, C; Wang, CF; Gerner, P
Anesthesia and Analgesia, 107(5): 1587-1591.
Postoperative pain therapy after radical prostatectomy with and without epidural analgesia
Ozgur, E; Dagtekin, O; Straub, K; Engelmann, U; Gerbershagen, HJ
Urologe, 48(): 1182-1188.
Anaesthesia, surgery, and challenges in postoperative recovery
Kehlet, H; Dahl, JB
Lancet, 362(): 1921-1928.

Life Sciences
Preemptive effects of intrathecal cyclooxygenase inhibitor or nitric oxide synthase inhibitor on thermal hypersensitivity following peripheral nerve injury
Lui, PW; Lee, CH
Life Sciences, 75(): 2527-2538.
Journal of Clinical Psychiatry
Preemptive analgesia: Is pain less costly when you pre-pay for it?
Stahl, SM
Journal of Clinical Psychiatry, 65(): 1591-1592.

Ketamine and postoperative pain - a quantitative systematic review of randomised trials
Elia, N; Tramer, MR
Pain, 113(): 61-70.
Anesthesia and Analgesia
Intrathecal and epidural anesthesia and analgesia for cardiac surgery
Chaney, MA
Anesthesia and Analgesia, 102(1): 45-64.
Current Therapeutic Research-Clinical and Experimental
Comparison of preemptive analgesic effects of a single dose of nonopioid analgesics for pain management after ambulatory surgery: A prospective, randomized, single-blind study in Turkish patients
Sener, M; Pektas, ZO; Yilmaz, I; Turkoz, A; Uckan, S; Donmez, A; Arslan, G
Current Therapeutic Research-Clinical and Experimental, 66(6): 541-551.
Acta Anaesthesiologica Scandinavica
A qualitative systematic review of peri-operative dextromethorphan in post-operative pain
Duedahl, TH; Romsing, J; Moiniche, S; Dahl, JB
Acta Anaesthesiologica Scandinavica, 50(1): 1-13.
Journal of Pain
The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients
Cohen, SP; Verdolin, MH; Chang, AS; Kurihara, C; Morlando, BJ; Mao, JR
Journal of Pain, 7(6): 391-398.
Journal of Veterinary Pharmacology and Therapeutics
Postoperative analgesia in dogs receiving epidural morphine plus medetomidine
Pacharinsak, C; Greene, SA; Keegan, RD; Kalivas, PW
Journal of Veterinary Pharmacology and Therapeutics, 26(1): 71-77.

Danish Medical Bulletin
Inguinal hernia repair: anaesthesia, pain and convalescence
Callesen, T
Danish Medical Bulletin, 50(3): 203-218.

Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
New insights in postoperative pain therapy
Brack, A; Bottiger, BW; Schafer, M
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 39(3): 157-164.
Anesthesia and Analgesia
Persistent pain as a disease entity: Implications for clinical management
Siddall, PJ; Cousins, MJ
Anesthesia and Analgesia, 99(2): 510-520.
Acta Anaesthesiologica Scandinavica
Analgesic effects of preincisional administration of dextromethorphan and tenoxicam following laparoscopic cholecystectomy
Yeh, CC; Wu, CT; Lee, MS; Yu, JC; Yang, CP; Lu, CH; Wong, CS
Acta Anaesthesiologica Scandinavica, 48(8): 1049-1053.
British Journal of Anaesthesia
Effect of pre-emptive ketamine on sensory changes and postoperative pain after thoracotomy: comparison of epidural and intramuscular routes
Ozyalcin, NS; Yucel, A; Camlica, H; Dereli, N; Andersen, OK; Arendt-Nielsen, L
British Journal of Anaesthesia, 93(3): 356-361.
Anesthesia and Analgesia
The changing role of non-opioid analgesic techniques in the management of postoperative pain
White, PF
Anesthesia and Analgesia, 101(5): S5-S22.

Pediatric Anesthesia
Effect of an intravenous single dose of ketamine on postoperative pain in tonsillectomy patients
Da Conceicao, MJ; Da Conceicao, DB; Leao, CC
Pediatric Anesthesia, 16(9): 962-967.
Journal of Neurophysiology
Sympathetic sprouting near sensory neurons after nerve injury occurs preferentially on spontaneously active cells and is reduced by early nerve block
Xie, WR; Strong, JA; Li, HQ; Zhang, JM
Journal of Neurophysiology, 97(1): 492-502.
Preoperative sub-Tenon's capsule injection of ropivacaine in conjunction with general anesthesia in retinal detachment surgery
Bergman, L; Backmark, I; Ones, H; von Euler, C; Olivestedt, G; Kvanta, A; Steen, B; Seregard, S; Nilsson, B; Berglin, L
Ophthalmology, 114(): 2055-2060.
Auris Nasus Larynx
Pre-emptive analgesia for removal of nasal packing: A double-blind placebo controlled study
Yilmazer, C; Sener, M; Yilmaz, I; Erkan, AN; Cagici, CA; Donmez, A; Arslan, G; Ozluoglu, LN
Auris Nasus Larynx, 34(4): 471-475.
British Journal of Anaesthesia
Preventive effects of perioperative parecoxib on post-discectomy pain
Riest, G; Peters, J; Weiss, M; Dreyer, S; Klassen, PD; Stegen, B; Bello, A; Eikermann, M
British Journal of Anaesthesia, 100(2): 256-262.
Acta Anaesthesiologica Scandinavica
Analgesia and discharge following preincisional ilioinguinal and iliohypogastric nerve block combined with general or spinal anaesthesia for inguinal herniorrhaphy
Toivonen, J; Permi, J; Rosenberg, PH
Acta Anaesthesiologica Scandinavica, 48(4): 480-485.
Javma-Journal of the American Veterinary Medical Association
Prevalence and characteristics of pain in dogs and cats examined as outpatients at a veterinary teaching hospital
Muir, WW; Wiese, AJ; Wittum, TE
Javma-Journal of the American Veterinary Medical Association, 224(9): 1459-1463.

Opioid-induced hyperalgesia. Pathophysiology and clinical relevance
Koppert, W
Anaesthesist, 53(5): 455-466.

Anesthesia and Analgesia
The intravenous ketamine test: A predictive response tool for oral dextromethorphan treatment in neuropathic pain
Cohen, SP; Chang, AS; Larkin, T; Mao, JR
Anesthesia and Analgesia, 99(6): 1753-1759.
Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model
Koppert, W; Ihmsen, H; Korber, N; Wehrfritz, A; Sittl, R; Schmelz, M; Schuttler, J
Pain, 118(): 15-22.
Iranian Red Crescent Medical Journal
Preemptive Effects of Lidocain on Postoperative Pain in Patients Undergoing Disc Operation: A Randomized, Double Blind, Placebo-Controlled Clinical Trial
Fakharian, E; Fazel, MR; Tabesh, H; Masoud, SA
Iranian Red Crescent Medical Journal, 11(1): 37-41.

Anz Journal of Surgery
Post-surgical neuropathic pain
Shipton, E
Anz Journal of Surgery, 78(7): 548-555.
Anesthesia and Analgesia
An evaluation of the postoperative antihyperalgesic and analgesic effects of intrathecal clonidine administered during elective cesarean delivery
Lavand'homme, PM; Roelants, F; Waterloos, H; COllet, V; De Kock, MF
Anesthesia and Analgesia, 107(3): 948-955.
Pain and quality of life for living donors after nephrectomy
Gottschalk, A; Gotz, J; Zenz, M
Schmerz, 23(5): 502-509.
British Journal of Anaesthesia
Efficacy and safety of different techniques of paravertebral block for analgesia after thoracotomy: a systematic review and metaregression
Kotze, A; Scally, A; Howell, S
British Journal of Anaesthesia, 103(5): 626-636.
Regional Anesthesia and Pain Medicine
Mechanisms for pain caused by incisions
Zahn, PK; Pogatzki, EM; Brennan, TJ
Regional Anesthesia and Pain Medicine, 27(5): 514-516.
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
Anesthesia in thoracic surgery
Wiedemann, K; Mannle, C; Layer, M; Herth, F
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 39(): 616-650.
Making progress in the management of postoperative pain: A review of the cyclooxygenase 2-specific inhibitors
Stephens, JM; Pashos, CL; Haider, S; Wong, JM
Pharmacotherapy, 24(): 1714-1731.

Javma-Journal of the American Veterinary Medical Association
Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists
Pozzi, A; Muir, WW; Traverso, F
Javma-Journal of the American Veterinary Medical Association, 228(1): 53-60.

Proceedings of the 8th Biennial Congress of the Asian & Oceanic Society of Regional Anesthesia and Pain Medicine
Pre-emptive analgesia
Scott, DA
Proceedings of the 8th Biennial Congress of the Asian & Oceanic Society of Regional Anesthesia and Pain Medicine, (): 43-45.

Acta Anaesthesiologica Scandinavica
Bowel function after bowel surgery: morphine with ketamine or placebo; a randomized controlled trial pilot study
Mckay, WP; Donais, P
Acta Anaesthesiologica Scandinavica, 51(9): 1166-1171.
European Journal of Cancer
A review of the literature on post-operative pain in order cancer patients
Looi, YC; Audisio, RA
European Journal of Cancer, 43(): 2222-2230.
Javma-Journal of the American Veterinary Medical Association
Evaluation of epidural administration of morphine or morphine and bupivacaine for postoperative analgesia after premedication with an opioid analgesic and orthopedic surgery in dogs
Kona-Boun, JJ; Cuvelliez, S; Troncy, E
Javma-Journal of the American Veterinary Medical Association, 229(7): 1103-1112.

Journal of Molecular Neuroscience
Effect of gabapentin on c-Fos expression in the CNS after paw surgery in rats
Kazi, JA; Gee, CF
Journal of Molecular Neuroscience, 32(3): 228-234.
European Journal of Cardio-Thoracic Surgery
Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention
Wildgaard, K; Ravn, J; Kehlet, H
European Journal of Cardio-Thoracic Surgery, 36(1): 170-180.
European Journal of Cardio-Thoracic Surgery
A prospective study of analgesic quality after a thoracotomy: paravertebral block with ropivacaine before and after rib spreading
Fibla, JJ; Molins, L; Mier, JM; Sierra, A; Vidal, G
European Journal of Cardio-Thoracic Surgery, 36(5): 901-905.
Progres En Urologie
Effect of wound infiltration of ropivacaine in postoperative pain after extraperitoneal laparoscopic radical prostatectomy
Berthon, N; Plainard, X; Cathelineau, X; Rozet, F; Cathala, N; Mombet, A; Galiano, M; Prapotnich, D; Barret, E; Vallancien, G
Progres En Urologie, 20(6): 435-439.
Anesthesia and Analgesia
A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia
McCartney, CJL; Sinha, A; Katz, J
Anesthesia and Analgesia, 98(5): 1385-1400.
Anesthesia and analgesia in addicts
Jage, J; Heid, F
Anaesthesist, 55(6): 611-+.
Perioperative pain management in orthopaedics
Schulz, A; Jerosch, J
Orthopade, 36(1): 32-+.
International Journal of Oral and Maxillofacial Surgery
A comparison of pre-emptive analgesic efficacy of diflunisal and lornoxicam for postoperative pain management: a prospective, randomized, single-blind, crossover study
Pektas, ZO; Sener, M; Bayram, B; Eroglu, T; Bozdogan, N; Donmez, A; Arslan, G; Uckan, S
International Journal of Oral and Maxillofacial Surgery, 36(2): 123-127.
European Journal of Obstetrics Gynecology and Reproductive Biology
Preoperative analgesia with local lidocaine infiltration for abdominal hysterectomy pain management
Lowenstein, L; Zimmer, EZ; Deutsch, M; Paz, Y; Yaniv, D; Jakobi, P
European Journal of Obstetrics Gynecology and Reproductive Biology, 136(2): 239-242.
Vlaams Diergeneeskundig Tijdschrift
Perioperative pain: physiology and pathophysiology
Bosmans, T; Doom, M; Gasthuys, F; Simoens, P; Van Ham, L; Polis, I
Vlaams Diergeneeskundig Tijdschrift, 78(5): 302-313.

Pediatric Anesthesia
A pilot study of the rectus sheath block for pain control after umbilical hernia repair
Isaac, LA; McEwen, J; Hayes, JA; Crawford, MW
Pediatric Anesthesia, 16(4): 406-409.
American Journal of Veterinary Research
Evaluation of intravenous administration of meloxicam for perioperative pain management following stifle joint surgery in dogs
Budsberg, SC; Cross, AR; Quandt, JE; Pablo, LS; Runk, AR
American Journal of Veterinary Research, 63(): 1557-1563.

Urologia Internationalis
Patient-controlled epidural analgesia after major urologic surgeries
Aribogan, A; Doruk, N; Aridogan, A; Akin, S; Balcioglu, O
Urologia Internationalis, 71(2): 168-175.
Veterinary Surgery
Analgesic comparison of meloxicam or ketoprofen for orthopedic surgery in dogs
Deneuche, AJ; Dufayet, C; Goby, L; Fayolle, P; Desbois, C
Veterinary Surgery, 33(6): 650-660.
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
Pharmacological PONV-control: Prevention or treatment
Tramer, MR
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 40(8): 493-497.
Annals of Thoracic Surgery
Efficacy of methods of intercostal nerve blockade for pain relief after thoracotomy
Detterbeck, FC
Annals of Thoracic Surgery, 80(4): 1550-1559.
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Pain management after ambulatory' surgery - Where is the disconnect?
White, PF
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 55(4): 201-207.

Australian Veterinary Journal
Effects of meloxicam or tolfenamic acid administration on the pain and stress responses of Merino lambs to mulesing
Paull, DR; Lee, C; Atkinson, SJ; Fisher, AD
Australian Veterinary Journal, 86(8): 303-311.
Acta Anaesthesiologica Scandinavica
Wound infiltration with magnesium sulphate and ropivacaine mixture reduces postoperative tramadol requirements after radical prostatectomy
Tauzin-Fin, P; Sesay, M; Svartz, L; Krol-Houdek, MC; Maurette, P
Acta Anaesthesiologica Scandinavica, 53(4): 464-469.
Anaesthesia Pain Intensive Care and Emergency Medicine - A.P.I.C.E, Vol 1 and 2
Pain relief by ketamine
Himmelseher, S; Kochs, E
Anaesthesia Pain Intensive Care and Emergency Medicine - A.P.I.C.E, Vol 1 and 2, (): 903-913.

New Zealand Veterinary Journal
Current attitudes to, and use of, peri-operative analgesia in dogs and cats by veterinarians in New Zealand
Williams, VM; Lascelles, BDX; Robson, MC
New Zealand Veterinary Journal, 53(3): 193-202.

British Journal of Anaesthesia
Low dose of S(+)-ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo
Benrath, J; Brechtel, C; Sandkuhler, J
British Journal of Anaesthesia, 95(4): 518-523.
Regional Anesthesia and Pain Medicine
A Preoperative retrobulbar block in patients undergoing scleral buckling reduces pain, endogenous stress response, and improves vigilance
Vogt, G; Heiden, M; Losche, CC; Lipfert, P
Regional Anesthesia and Pain Medicine, 28(6): 521-527.
Annales Francaises D Anesthesie Et De Reanimation
Low doses ketamine: antihyperalgesic drug, non-analgesic
Richebe, P; Rivat, C; Rivalan, B; Maurette, P; Simonnet, G
Annales Francaises D Anesthesie Et De Reanimation, 24(): 1349-1359.
Anesthesia and Analgesia
The efficacy of thoracic epidural neostigmine infusion after thoracotomy
Chia, YY; Chang, TH; Liu, K; Chang, HC; Ko, NH; Wang, YM
Anesthesia and Analgesia, 102(1): 201-208.
British Journal of Anaesthesia
Premedication with controlled-release oxycodone does not improve management of postoperative pain after day-case gynaecological laparoscopic surgery
Jokela, R; Ahonen, J; Valjus, M; Seppala, T; Korttila, K
British Journal of Anaesthesia, 98(2): 255-260.
Veterinary Anaesthesia and Analgesia
Nonsteroidal anti-inflammatory drugs in cats: a review
Duncan, B; Lascelles, X; Court, MH; Hardie, EM; Robertson, SA
Veterinary Anaesthesia and Analgesia, 34(4): 228-250.
Veterinary Journal
Pain mechanisms and their implication for the management of pain in farm and companion animals
Vinuela-Fernandez, I; Jones, E; Welsh, EM; Fleetwood-Walker, SM
Veterinary Journal, 174(2): 227-239.
Journal of Clinical Anesthesia
The influence of timing of systemic ketamine administration on postoperative morphine consumption
Bilgin, H; Ozcan, B; Bilgin, T; Kerimoglu, B; Uckunkaya, N; Toker, A; Alev, T; Osma, S
Journal of Clinical Anesthesia, 17(8): 592-597.
Acta Obstetricia Et Gynecologica Scandinavica
Effect of presurgical local infiltration of levobupivacaine in the surgical field on postsurgical wound pain in laparoscopic gynecological surgery
Alessandri, F; Lijoi, D; Mistrangelo, E; Nicoletti, A; Ragni, N
Acta Obstetricia Et Gynecologica Scandinavica, 85(7): 844-849.
Anasthesiologie & Intensivmedizin
Spinal mechanisms of postoperative pain
Zahn, PK
Anasthesiologie & Intensivmedizin, 47(): 517-527.

Journal of Bone and Joint Surgery-American Volume
Preventing the development of chronic pain after orthopaedic surgery with preventive multimodal analgesic techniques
Reuben, SS; Buvanendran, A
Journal of Bone and Joint Surgery-American Volume, 89A(6): 1343-1358.

Current Opinion in Investigational Drugs
Multimodal analgesia: Its role in preventing postoperative pain
White, PF
Current Opinion in Investigational Drugs, 9(1): 76-82.

Drugs for postoperative analgesia: routine and new aspects. Part1: Non-opioids
Jage, J; Laufenberg-Feldmann, R; Heid, F
Anaesthesist, 57(4): 382-+.
Minerva Anestesiologica
Updating postoperative pain management: from multimodal to context-sensitive treatment
Fanelli, G; Berti, M; Baciarello, M
Minerva Anestesiologica, 74(9): 489-500.

Annals of Thoracic Surgery
Acute pain management for patients undergoing thoracotomy
Soto, RG; Fu, ES
Annals of Thoracic Surgery, 75(4): 1349-1357.
PII S0003-4975(02)04647-7
Acta Anaesthesiologica Scandinavica
Influence of the cortical electrical activity level during general anaesthesia on the severity of immediate postoperative pain in the morbidly obese
Gurman, GM; Popescu, M; Weksler, N; Steiner, O; Avinoah, E; Porath, A
Acta Anaesthesiologica Scandinavica, 47(7): 804-808.

British Medical Bulletin
Pre-emptive analgesia
Dahl, JB; Moiniche, S
British Medical Bulletin, 71(1): 13-27.
Clinical Nutrition
Enhanced recovery after surgery: A consensus review of clinical care for patients undergoing colonic resection
Fearon, KCH; Ljungqvist, O; Von Meyenfeldt, M; Revhaug, A; Dejong, CHC; Lassen, K; Nygren, J; Hausel, J; Soop, M; Andersen, J; Kehlet, H
Clinical Nutrition, 24(3): 466-477.
British Journal of Anaesthesia
Chronic postoperative pain: the case of inguinal herniorrhaphy
Aasvang, E; Kehlet, H
British Journal of Anaesthesia, 95(1): 69-76.
Journal of Arthroplasty
The effect of a new multimodal perioperative anesthetic regimen on postoperative pain, side effects, rehabilitation, and length of hospital stay after total joint arthroplasty
Peters, CL; Shirley, B; Erickson, J
Journal of Arthroplasty, 21(6): 132-138.
Anesthesia and Analgesia
The influence of timing of administration on the analgesic efficacy of parecoxib in orthopedic surgery
Martinez, V; Belbachir, A; Jaber, A; Cherif, K; Jamal, A; Ozier, Y; Sessler, DI; Chauvin, M; Fletcher, D
Anesthesia and Analgesia, 104(6): 1521-1527.
Current Opinion in Investigational Drugs
Multimodal pain management - The future is now!
White, PF
Current Opinion in Investigational Drugs, 8(7): 517-518.

Pediatric Anesthesia
The preventative analgesic effect of preincisional peritonsillar infiltration of two low doses of ketamine for postoperative pain relief in children following adenotonsillectomy. A randomized, double-blind, placebo-controlled study
Honarmand, A; Safavi, MR; Jamshidi, M
Pediatric Anesthesia, 18(6): 508-514.
Anesthesia and Analgesia
Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: A prospective, randomized, double-blind, controlled study
Zakine, J; Samarcq, D; Lorne, E; Moubarak, M; Montravers, P; Beloucif, S; Dupont, H
Anesthesia and Analgesia, 106(6): 1856-1861.
Australian Journal of Experimental Agriculture
Effectiveness of non-steroidal anti-inflammatory drugs and epidural anaesthesia in reducing the pain and stress responses to a surgical husbandry procedure (mulesing) in sheep
Paull, DR; Colditz, IG; Lee, C; Atkinson, SJ; Fisher, AD
Australian Journal of Experimental Agriculture, 48(): 1034-1039.
Journal of the American Academy of Dermatology
An analysis of pain and analgesia after Mohs micrographic surgery
Firoz, BF; Goldberg, LH; Arnon, O; Mamelak, AJ
Journal of the American Academy of Dermatology, 63(1): 79-86.
Acta Anaesthesiologica Scandinavica
'Protective premedication': an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain
Dahl, JB; Mathiesen, O; Moiniche, S
Acta Anaesthesiologica Scandinavica, 48(9): 1130-1136.
Canadian Veterinary Journal-Revue Veterinaire Canadienne
Understanding the pathophysiology of perioperative pain
Lemke, KA
Canadian Veterinary Journal-Revue Veterinaire Canadienne, 45(5): 405-413.

Polish Journal of Pharmacology
Influence of pre-operative ketoprofen administration (preemptive analgesia) on analgesic requirement and the level of prostaglandins in the early postoperative period
Wnek, W; Zajaczkowska, R; Wordliczek, J; Dobrogowski, J; Korbut, R
Polish Journal of Pharmacology, 56(5): 547-552.

Anesthesia and Analgesia
Update on acute pain management
Rowlingson, JC
Anesthesia and Analgesia, (): 95-106.

Persistent postsurgical pain: risk factors and prevention
Kehlet, H; Jensen, TS; Woolf, CJ
Lancet, 367(): 1618-1625.

Clinical Drug Investigation
Premedication with Sublingual Morphine Sulphate in Abdominal Surgery
Campiglia, L; Cappellini, I; Consales, G; Borracci, T; Vitali, L; Gallerani, E; Boninsegni, P; Mediati, RD; De Gaudio, AR
Clinical Drug Investigation, 29(): 25-30.

Archives of Orthopaedic and Trauma Surgery
The effects of pre-emptive analgesia with bupivacaine on acute post-laminectomy pain
Mordeniz, C; Torun, F; Soran, AF; Beyazoglu, O; Karabag, H; Cakir, A; Yucetas, SC
Archives of Orthopaedic and Trauma Surgery, 130(2): 205-208.
Journal of Bone and Joint Surgery-American Volume
Acute pain following musculoskeletal injuries and orthopaedic surgery - Mechanisms and management
Ekman, EF; Koman, LA
Journal of Bone and Joint Surgery-American Volume, 86A(6): 1316-1327.

British Journal of Oral & Maxillofacial Surgery
A double-blind randomised controlled clinical trial of the effect of preoperative ibuprofen, diclofenac, paracetamol with codeine and placebo tablets for relief of postoperative pain after removal of impacted third molars
Joshi, A; Parara, E; Macfarlane, TV
British Journal of Oral & Maxillofacial Surgery, 42(4): 299-306.
Expert Opinion on Pharmacotherapy
Pharmacological interventions and concepts of fast-track perioperative medical care for enhanced recovery programs
Kranke, P; Redel, A; Schuster, F; Muellenbach, R; Eberhart, L
Expert Opinion on Pharmacotherapy, 9(9): 1541-1564.
Anesthesia and Analgesia
Local Administration of Morphine for Analgesia After Autogenous Anterior or Posterior Iliac Crest Bone Graft Harvest for Spinal Fusion: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study
Wai, EK; Sathiaseelan, S; O'Neil, J; Simchison, BL
Anesthesia and Analgesia, 110(3): 928-933.
Anesthesia and Analgesia
Preoperative interscalene block for elective shoulder surgery: Loss of benefit over early postoperative block after patient discharge to home
Wurm, WH; Concepcion, M; Sternlicht, A; Carabuena, JM; Robelen, G; Goudas, LC; Strassels, SA; Carr, DB
Anesthesia and Analgesia, 97(6): 1620-1626.
Veterinary Anaesthesia and Analgesia
Systemic lidocaine infusion as an analgesic for intraocular surgery in dogs: a pilot study
Smith, LJ; Bentley, E; Shih, A; Miller, PE
Veterinary Anaesthesia and Analgesia, 31(1): 53-63.

Anesthesia and Analgesia
Preoperative sciatic nerve block decreases mechanical allodynia more in young rats: Is preemptive analgesia developmentally modulated?
Ririe, DG; Barclay, D; Prout, H; Tong, CY; Tobin, JR; Eisenach, JC
Anesthesia and Analgesia, 99(1): 140-145.
Neuroscience Research
Preemptive analgesia by zaltoprofen that inhibits bradykinin action and cyclooxygenase in a post-operative pain model
Muratani, T; Doi, Y; Nishimura, W; Nishizawa, M; Minami, T; Ito, S
Neuroscience Research, 51(4): 427-433.
World Journal of Surgery
Groin hernia repair: Anesthesia
Kehlet, H; Aasvang, E
World Journal of Surgery, 29(8): 1058-1061.
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics
The effects on postoperative oral surgery pain by varying NSAID administration times: Comparison on effect of preemptive analgesia
Jung, YS; Kim, MK; Um, YJ; Park, HS; Lee, EW; Kang, JW
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, 100(5): 559-563.
Veterinary Research Communications
Multimodal and balanced analgesia
Corletto, F
Veterinary Research Communications, 31(): 59-63.
Ophthalmic Surgery Lasers & Imaging
Preemptive sub-Tenon's anesthesia for Pars Plana Vitrectomy under general anesthesia: Is it effective?
Smiddy, WE; Gayer, S
Ophthalmic Surgery Lasers & Imaging, 39(5): 438.

Annales Francaises D Anesthesie Et De Reanimation
Ropivacaine infiltration during breast cancer surgery: Postoperative acute and chronic pain effect
Baudry, G; Steghens, A; Laplaza, D; Koeberle, P; Bachour, K; Bettinger, G; Combier, F; Samain, E
Annales Francaises D Anesthesie Et De Reanimation, 27(): 979-986.
Pain Medicine
The Effect of Preemptive Analgesia in Postoperative Pain Relief-A Prospective Double-Blind Randomized Study
Hariharan, S; Moseley, H; Kumar, A; Raju, S
Pain Medicine, 10(1): 49-53.
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Pre- and intraoperative epidural ropivacaine have no early preemptive analgesic effect in major gynecological tumour surgery
Burmeister, MA; Gottschalk, A; Frcitag, M; Horn, EP; Bohme, C; Becker, C; Standl, TG
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 50(6): 568-573.

European Journal of Cardio-Thoracic Surgery
Early postoperative pain management after thoracic surgery; pre- and postoperative versus postoperative epidural analgesia: a randomised study
Yegin, A; Erdogen, A; Kayacan, N; Karsli, B
European Journal of Cardio-Thoracic Surgery, 24(3): 420-424.
A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty
Fischer, HBJ; Simanski, CJP; Sharp, C; Bonnet, F; Camu, F; Neugebauer, EAM; Rawal, N; Joshi, GP; Schug, SA; Kehlet, H
Anaesthesia, 63(): 1105-1123.
Australian Dental Journal
Pre-emptive ibuprofen arginate in third molar surgery: a double-blind randomized controlled crossover clinical trial
Lau, SL; Chow, RLK; Yeung, RWK; Samman, N
Australian Dental Journal, 54(4): 355-360.
Perisurgical amitriptyline produces a preventive effect on afferent hypersensitivity following spared nerve injury
Arsenault, A; Sawynok, J
Pain, 146(3): 308-314.
Acta Anaesthesiologica Scandinavica
Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: A systematic review of randomized studies
Straube, S; Derry, S; McQuay, HJ; Moore, RA
Acta Anaesthesiologica Scandinavica, 49(5): 601-613.
Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery
Intermittent injection of bupivacaine into the margin or the cavity after reduction mammaplasty
Holmgren, RT; Tarpila, E
Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, 39(4): 218-221.
British Journal of Anaesthesia
Pre-emptive analgesia with thoracic paravertebral blockade?
Lonnqvist, PA
British Journal of Anaesthesia, 95(6): 727-728.
Anesthesia and Analgesia
Preincisional treatment to prevent pain after ambulatory hernia surgery
Pavlin, DJ; Horvath, KD; Pavlin, EG; Sima, K
Anesthesia and Analgesia, 97(6): 1627-1632.
Anesthesia and Analgesia
Does a preemptive block of the great auricular nerve improve postoperative analgesia in children undergoing tympanomastoid surgery?
Suresh, S; Barcelona, SL; Young, NM; Heffner, CL; Cote, CJ
Anesthesia and Analgesia, 98(2): 330-333.
Anesthesia and Analgesia
Characterization of a new animal model for evaluation of persistent postthoracotomy pain
Buvanendran, A; Kroin, JS; Kerns, JM; Nagalla, SNK; Tuman, KJ
Anesthesia and Analgesia, 99(5): 1453-1460.
Brain Research Reviews
The importance of 'awareness' for understanding fetal pain
Mellor, DJ; Diesch, TJ; Gunn, AJ; Bennet, L
Brain Research Reviews, 49(3): 455-471.
Brain Research
Enhancement of morphine antinociception with the peptide N-methyl-D-aspartate receptor antagonist [Ser(1)]-histogranin in the rat formalin test
Hama, A; Basler, A; Sagen, J
Brain Research, 1095(): 59-64.
Bmc Musculoskeletal Disorders
Perioperative celecoxib administration for pain management after total knee arthroplasty - A randomized, controlled study
Huang, YM; Wang, CM; Wang, CT; Lin, WP; Horng, LC; Jiang, CC
Bmc Musculoskeletal Disorders, 9(): -.
European Journal of Cardio-Thoracic Surgery
Pre-emptive local anesthesia for needlescopic video-assisted thoracic surgery: a randomized controlled trial
Sihoe, ADL; Manlulu, AV; Lee, TW; Thung, KH; Yim, APC
European Journal of Cardio-Thoracic Surgery, 31(1): 103-108.
CNS Drugs
Perioperative pain management
Pyati, S; Gan, TJ
CNS Drugs, 21(3): 185-211.

Anesthesia and Analgesia
Perioperative versus postoperative celecoxib on patient outcomes after major plastic surgery procedures
Sun, T; Sacan, O; White, PF; Coleman, J; Rohrich, RJ; Kenkel, JM
Anesthesia and Analgesia, 106(3): 950-958.
Anesthesia and Analgesia
Perioperative Analgesia: What Do We Still Know?
White, PF; Kehlet, H; Liu, S
Anesthesia and Analgesia, 108(5): 1364-1367.
The management of pain in the burns unit
Richardson, P; Mustard, L
Burns, 35(7): 921-936.
Regional Anesthesia and Pain Medicine
Evaluation of the Addition of Bupivacaine to Intrathecal Morphine and Fentanyl for Postoperative Pain Management in Laparascopic Liver Resection
Nguyen, M; Vandenbroucke, F; Roy, JD; Beaulieu, D; Seal, RF; Lapointe, R; Dagenais, M; Roy, A; Massicotte, L
Regional Anesthesia and Pain Medicine, 35(3): 261-266.
Wiener Klinische Wochenschrift
Preoperative oral administration of fast-release morphine sulfate reduces postoperative piritramide consumption
Reiter, A; Zulus, E; Hartmann, T; Hoerauf, K
Wiener Klinische Wochenschrift, 115(): 417-420.

Anesthesia and Analgesia
Preoperative rofecoxib oral suspension as an analgesic adjunct after lower abdominal surgery: The effects on effort-dependent pain and pulmonary function
Sinatra, RS; Shen, QHJ; Halaszynski, T; Luther, MA; Shaheen, Y
Anesthesia and Analgesia, 98(1): 135-140.
Annales Francaises D Anesthesie Et De Reanimation
Increase in bispectral index induced by antihyperalgesic dose of ketamine
Chaaben, K; Marret, E; Lamonerie, L; Lembert, N; Bonnet, F
Annales Francaises D Anesthesie Et De Reanimation, 23(5): 513-516.
International Journal of Oral and Maxillofacial Surgery
Preoperative ketorolac has a preemptive effect for postoperative third molar surgical pain
Ong, KS; Seymour, RA; Chen, FG; Ho, VCL
International Journal of Oral and Maxillofacial Surgery, 33(8): 771-776.
Impact on postoperative pain of long-lasting pre-emptive epidural analgesia before total hip replacement: a prospective, randomised, double-blind study
Klasen, J; Haas, M; Graf, S; Harbach, H; Quinzio, L; Jurgensen, I; Hempelmann, G
Anaesthesia, 60(2): 118-123.

Current Drug Targets
Analgesia in PACU: Nonsteroidal anti-inflammatory drugs
Della Rocca, G; Chiarandini, P; Pietropaoli, P
Current Drug Targets, 6(7): 781-787.

Anesthesia and Analgesia
Preemptive analgesia at the crossroad
Kissin, I
Anesthesia and Analgesia, 100(3): 754-756.
Anesthesia and Analgesia
The efficacy of preemptive analgesia for acute postoperative pain management: A meta-analysis
Ong, CKS; Lirk, P; Seymour, RA; Jenkins, BJ
Anesthesia and Analgesia, 100(3): 757-773.
Journal of Neuroscience
Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release
Kondo, I; Marvizon, JCG; Song, BB; Salgado, F; Codeluppi, S; Hua, XY; Yaksh, TL
Journal of Neuroscience, 25(): 3651-3660.
Regional Anesthesia and Pain Medicine
Long-Lasting Analgesic Effects of Intraoperative Thoracic Epidural With Bupivacaine for Liver Resection
Mondor, ME; Massicotte, L; Beaulieu, D; Roy, JD; Lapointe, R; Dagenais, M; Roy, A
Regional Anesthesia and Pain Medicine, 35(1): 51-56.
European Journal of Cardio-Thoracic Surgery
Pre-emptive local analgesia in video-assisted thoracic surgery sympathectomy
Fiorelli, A; Vicidomini, G; Laperuta, P; Busiello, L; Perrone, A; Napolitano, F; Messina, G; Santini, M
European Journal of Cardio-Thoracic Surgery, 37(3): 588-593.
Annales Francaises D Anesthesie Et De Reanimation
Efficiency of bupivacaine wound subfasciale infiltration in reduction of postoperative pain after inguinal hernia surgery
Mounir, K; Bensghir, M; Elmoqaddem, A; Massou, S; Belyamani, L; Atmani, M; Azendour, H; Kamili, ND
Annales Francaises D Anesthesie Et De Reanimation, 29(4): 274-278.
European Journal of Pharmacology
Prolonged analgesic effect of amitriptyline base on thermal hyperalgesia in an animal model of neuropathic pain
Huang, KL; Shieh, JP; Chu, CC; Cheng, KI; Wang, JJ; Lin, MT; Yeh, MY
European Journal of Pharmacology, 702(): 20-24.
Pain Physician
Pre-Emptive and Multi-Modal Perioperative Pain Management May Improve Quality of Life in Patients Undergoing Spinal Surgery
Lee, BH; Park, JO; Suk, KS; Kim, TH; Lee, HM; Park, MS; Lee, SH; Park, S; Lee, JY; Ko, SK; Moon, SH
Pain Physician, 16(3): E217-E226.

CNS Neuroscience & Therapeutics
Ketamine in Pain Management
Persson, J
CNS Neuroscience & Therapeutics, 19(6): 396-402.
World Journal of Surgery
Guidelines for Perioperative Care for Pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS((R))) Society Recommendations
Lassen, K; Coolsen, MME; Slim, K; Carli, F; de Aguilar-Nascimento, JE; Schafer, M; Parks, RW; Fearon, KCH; Lobo, DN; Demartines, N; Braga, M; Ljungqvist, O; Dejong, CHC
World Journal of Surgery, 37(2): 240-258.
Journal of Cranio-Maxillofacial Surgery
Comparative study of tramadol combined with dexamethasone and diclofenac sodium in third-molar surgery
Santos, JASD; da Silva, LCF; Santos, TD; Menezes, LR; Oliveira, ACD; Brandao, JRMCB
Journal of Cranio-Maxillofacial Surgery, 40(8): 694-700.
Clinical Nutrition
Guidelines for perioperative care for pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS (R)) Society recommendations
Lassen, K; Coolsen, MME; Slim, K; Carli, F; de Aguilar-Nascimento, JE; Schafer, M; Parks, RW; Fearon, KCH; Lobo, DN; Demartines, N; Braga, M; Ljungqvist, O; Dejong, CHC
Clinical Nutrition, 31(6): 817-830.
Journal of Obstetrics and Gynaecology
Pre-incisional, post-incisional and combined pre- and post-incisional local wound infiltrations with lidocaine in elective caesarean section delivery: A randomised clinical trial
Fouladi, RF; Navali, N; Abbassi, A
Journal of Obstetrics and Gynaecology, 33(1): 54-59.
Minerva Anestesiologica
Preoperative medication with oral morphine sulphate and postoperative pain
Borracci, T; Cappellini, I; Campiglia, L; Picciafuochi, F; Berti, J; Consales, G; De Gaudio, AR
Minerva Anestesiologica, 79(5): 525-533.

Pain Physician
Multivariate Prognostic Modeling of Persistent Pain Following Lumbar Discectomy
Hegarty, D; Shorten, G
Pain Physician, 15(5): 421-434.

Preemptive Analgesia: What Do We Do Now?
Gottschalk, A; Ochroch, E
Anesthesiology, 98(1): 280-281.

Effects of Halothane and Isoflurane on Hyperexcitability of Spinal Dorsal Horn Neurons after Incision in the Rat
Kawamata, M; Narimatsu, E; Kozuka, Y; Takahashi, T; Sugino, S; Niiya, T; Namiki, A
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